The International epidemiologic Databases to Evaluate AIDS in Southern Africa (IeDEA-SA) Collaboration has two key, related overarching research purposes related to the continuum of HIV care: (i) Global surveillance and evaluation of access to, effectiveness and outcomes of HIV care, antiretroviral therapy (ART) and HIV-related comorbidity programs (ii) Informing optimal treatment and implementation guidelines for HIV and its comorbidities in resource-limited settings. These areas will be examined across the life course from pregnancy to infants (HIV-infected and exposed), children, adolescents and adults, through regional and multiregional studies, within and beyond the IeDEA-SA consortium. The HIV epidemic is being transformed by massive ART expansion with corresponding declines in AIDS- related deaths and mother-to-child transmission, as well as ART improvements through access to better drugs, laboratory tests and health system innovations. To sustain and improve on hard-won reductions in HIV-related morbidity and mortality, we need to understand and optimize long-term HIV outcomes, including retention in care across life transitions, prevention and treatment of co-morbidity with infections and non-communicable diseases (e.g. cancer, cardiovascular disease and mental health disorders) and address the impact of substance abuse. Hence, IeDEA-SA specific aims are: 1)To study the continuum of HIV and tuberculosis (TB) care from diagnosis through to long-term outcomes; 2)To study co-infections (TB; hepatitis B), cardiovascular and metabolic co-morbidities; 3)To study the burden and care of cancers in HIV+ children and adults; 4) To study the HIV/ART continuum especially long-term outcomes in HIV+ mothers and their children, from pregnancy to exposed uninfected infants through to infected infants, children and adolescents; 5) To study mental health and mental health care provision; 6) To study substance use in adolescents and adults on ART, with a cross-cutting aim (7) To develop and apply state-of-the-art statistical methods, data harmonization standards, data collection and linkage tools. Routine cohort data of nearly 900,000 HIV+ individuals (60,000 <13 years old at enrolment) will be enhanced by linkage to mortality and other disease databases (e.g. cancer and TB) together with targeted additional data collection including tracing studies to minimize mortality and co-morbidity under-ascertainment, and site surveys. Throughout, statistical methods addressing biases in routine cohort data will be developed and used. Southern Africa is the epicenter of the HIV/TB epidemic (HIV prevalence of 10-27% across the region), and IeDEA-SA includes the largest number of adults and children. IeDEA-SA is well-placed to address the specific aims through its long and successful track-record of collaboration between the epidemiologic and operational leadership at the Universities of Bern and Cape Town, clinical, scientific and programmatic experts across Southern African and other IeDEA regions, as well as with WHO, UNAIDS and other information consumers.